MinireviewCase definition and classification of leukodystrophies and leukoencephalopathies
Introduction
Leukodystrophies are a heterogeneous group of disorders with highly variable clinical manifestations and pathologic mechanisms. They are loosely grouped together, usually based on the initial findings of white matter abnormalities in the central nervous system (CNS), historically based on gross pathology, and now often based on neuroimaging. There has never been, however, a formal definition or classification for this group of disorders. The term leukodystrophy technically refers to disorders with wasting (dystrophy) of the brain's white matter (leuko) and is traditionally reserved for heritable disorders, however there is lack of consensus on how this term should be applied.
Further complicating the definition of leukodystrophies, the related but distinct term “leukoencephalopathy” exists in the literature. This term has characteristically been applied to disorders seen in the context of toxic, acquired vascular or infectious insults, as well as inherited disorders. In addition, disparate terms, such as hypomyelination, demyelination and dysmyelination are in use, and are a source of confusion.
Given today's modern neuroimaging, genetic and histopathologic techniques, we sought a more precise definition of these terms and classification of those disorders to which they apply. A case definition is an essential component of any epidemiologic study in a group of disorders. This may seem an esoteric goal when compared to the overwhelming need for improved understanding of disease mechanisms and potential therapeutic strategies in these devastating disorders. However, the number of funded studies in leukodystrophies is currently small, partially due to the perceived rarity of these disorders, and while recent studies [1] suggest that the incidence of leukodystrophies may be higher than previously thought, the lack of a precise classification scheme makes conclusive calculations difficult. There is therefore a pressing need for study into the distributions of leukodystrophies, in order to justify support for research into these disorders based on their relevance to public health.
Here, we report the results of an iterative consensus-building effort among a panel of leukodystrophy experts aimed at precisely defining the definition, descriptive terms, inclusion criteria and exclusion criteria that characterize leukodystrophies. In addition, this group comprehensively identified those disorders that meet this established definition, based on the current understanding of disease mechanisms. We also define the term “genetic leukoencephalopathy (gLE),” to describe disorders that are heritable and result in white matter abnormalities but do not necessarily meet strict criteria as a leukodystrophy. Of note, leukodystrophies are genetic leukoencephalopathies, but not all genetic leukoencephalopathies qualify as leukodystrophies. We also discuss specific applications of this definition and the classification as well as limitations of the proposed system.
Section snippets
Panel of experts and the modified Delphi method
Experts in inherited disorders of the white matter of the brain are located throughout the world. For this reason, this study utilized the modified Delphi method, a systematic internet based approach reaching a consensus regarding a specific topic using iterative surveys of expert opinion [2], [3]. This approach permits consensus-building in circumstances where large face-to-face workgroups are not realistic.
Experts were selected based on their publication record and recognized expertise among
Definition of leukodystrophy
The following definition was achieved by the consensus of all participating authors.
Leukodystrophies are heritable disorders affecting the white matter of the central nervous system with or without peripheral nervous system involvement. These disorders have in common glial cell or myelin sheath abnormalities. Where known, neuropathology is primarily characterized by the involvement of oligodendrocytes, astrocytes and other non-neuronal cell types, although in many disorders the mechanism of
Discussion
We describe a systematic effort among a panel of thirteen experts currently working in the field of leukodystrophy to establish a comprehensive definition of leukodystrophies, and to classify disorders according to that definition. In addition, we also sought to characterize a class of gLEs, hereditary diseases of the central white matter with predominant systemic manifestations and/or predominant neuronal involvement that include leukodystrophies but also include disorders that do not meet the
Authorship and contributions
AV, FM, JG, FE, PL, PA, DR, MP, JLKVH, OBT, NIW, RS and MSvdK participated in the modified Delphi survey approach. JLS, MP, DT, HMH and GH provided support to survey moderating, researching and creating supporting tables and manuscript revision. AV, NIW, OBT and MSvdK provided critical review of the final manuscript.
Conflict of interest
MCP: Editorial: Journal of Child Neurology, Child Neurology Open (Editor-in-Chief), Journal of Inherited Metabolic Disease (Editor). Otherwise authors report no conflict of interest.
Funding sources
AV: Supported by grants from the National Institutes of Health, NINDS (1K08NS060695) and the Myelin Disorders Bioregistry Project. MCP: Funding: Actelion, National Institutes of Health, NINDS (U54NS065768-02), National MS Society. Actelion Pharmaceuticals: Research grants; travel expenses; consulting honoraria directed to Mayo Clinic; Genzyme (Sanofi): Consulting; Amicus: Data Safety Monitoring Board; Orphazyme (Denmark): Consulting; consulting honoraria directed to Mayo Clinic; Shire Human
Acknowledgments
The participation of MP and GH was supported by the Delman fund and the Neurogenetics Program at Children's National Health System. We would also like to thank Drs Yanick Crow and John Livingston for their valuable comments about Coats plus and CRMCC, and images of these disorders. The role of AV, GH and JL were supported by the Neurology Department at Children's National Health System and the Myelin Disorders Bioregistry Project. We also thank the Leukodystrophy Alliance for their support. GB
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